title: Bimodal effect on pancreatic β-cells of secretory products from normal or insulin-resistant human skeletal muscle.
abstract: OBJECTIVE
  Type 2 diabetes is characterized by insulin resistance with a relative deficiency in insulin secretion. This study explored the potential communication between insulin-resistant human skeletal muscle and primary (human and rat) β-cells.
  
  
  METHODS
  Human skeletal muscle cells were cultured for up to 24 h with tumor necrosis factor (TNF)-α to induce insulin resistance, and mRNA expression for cytokines was analyzed and compared with controls (without TNF-α). Conditioned media were collected and candidate cytokines were measured by antibody array. Human and rat primary β-cells were used to explore the impact of exposure to conditioned media for 24 h on apoptosis, proliferation, short-term insulin secretion, and key signaling protein phosphorylation and expression.
  
  
  RESULTS
  Human myotubes express and release a different panel of myokines depending on their insulin sensitivity, with each panel exerting differential effects on β-cells. Conditioned medium from control myotubes increased proliferation and glucose-stimulated insulin secretion (GSIS) from primary β-cells, whereas conditioned medium from TNF-α-treated insulin-resistant myotubes (TMs) exerted detrimental effects that were either independent (increased apoptosis and decreased proliferation) or dependent on the presence of TNF-α in TM (blunted GSIS). Knockdown of β-cell mitogen-activated protein 4 kinase 4 prevented these effects. Glucagon-like peptide 1 protected β-cells against decreased proliferation and apoptosis evoked by TMs, while interleukin-1 receptor antagonist only prevented the latter.
  
  
  CONCLUSIONS
  Taken together, these data suggest a possible new route of communication between skeletal muscle and β-cells that is modulated by insulin resistance and could contribute to normal β-cell functional mass in healthy subjects, as well as the decrease seen in type 2 diabetes.
authors.affiliation: Department of Genetic Medicine and Development, University Medical Center, University of Geneva, Geneva, Switzerland. karim.bouzakri@unige.ch.
authors.forename: Karim
authors.initials: K
authors.lastname: Bouzakri
authors.forename: Peter
authors.initials: P
authors.lastname: Plomgaard
authors.forename: Thierry
authors.initials: T
authors.lastname: Berney
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
authors.forename: Bente Karlund
authors.initials: BK
authors.lastname: Pedersen
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Halban
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases